These studies will critically examine the roles and mechanistic pathways which link these four nodal areas of cardiomyocyte signaling with the molecular physiology of heart failure in the context of genetically engineered animal model systems. Cause/effect relationships will be exacted using a combination of in vitro and in vivo genetic based strategies. The relevance of these pathways to acquired forms of heart disease and to genetically based forms of human dilated cardiomyopathy will be done collaboratively with other projects in the context of current SCOR Program. Finally, in order to directly examine the fidelity of these observations to human forms of heart failure, the relationship of single cell physiological observations obtained in these mouse model systems will be directly compared with those obtained in the human setting in collaboration with Bill Barry. Taken together, this project will form a bridge with the other projects that will examine other aspects of signaling pathways in acquired model systems which give rise to heart failure. Accordingly, the specific aims are as follows: 1. To identify the role of critical components in the stress-inducible myocyte survival pathway during the transition from compensatory hypertrophy to heart failure; 2. To determine the structural and functional role of MLP[ and related cytoskeletal pathways during the progression of genetically based forms of dilated cardiomyopathy and associated heart failure; 3. To identify the role of p38alpoha and p38beta pathways for cardiac myocyte hypertrophy and apoptosis during the course of cardiac failure; 4. To elucidate the role of SR Ca2+ regulatory pathways in functional rescue during various forms of cardiac hypertrophy and failure.